Table Of ContentIMMUNOLOGY
An International Series of Monographs
and Treatises
EDITED BY
F. J. DIXON, JR. HENRY G. KUNKEL
Division of Experimental Pathology The Rockefeller University
Scripps Clinic and Research Foundation New York, New York
La JoUa, California
G. J. V. Nossal and G. L. Ada, Antigens, Lymphoid Cells, and the Immune
Response. 1971
Barry D. Kahan and Ralph A. Reisfeld, Transplantation Antigens: Markers of
Biological Individuality. 1972
Alfred Nisonoff, John E. Hopper, and Susan B. Spring, The Antibody Molecule.
1975
David H. Katz, Lymphocyte Differentiation, Recognition, and Regulation. 1977
Norman Total, Autoimmunity: Genetic, Immunologic, Virologie, and Clinical
Aspects. 1978
Constantin A. Bona, Idiotypes and Lymphocytes. 1981
Idiotypes
and
Lymphocytes
CONSTANTIN A. BONA
Department of Microbiology
Mount Sinai School of Medicine
New York, New York
1981
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Bona, Constantin.
Idiotypes and lymphocytes.
(Immunology; v. 6)
Bibliography: p.
1. Immunoglobulin idiotypes. 2. Lymphocytes.
I. Title. II. Series. [DNLM: 1. Immunoglobulin
idiotypes—Immunology. 2. B-Lymphocytes—Immunology.
3. T-Lymphocytes—Immunology. QW 575 B697i]
QR186.7.B66 616.07'9 81-10759
ISBN 0-12-112950-0 AACR2
PRINTED IN THE UNITED STATES OF AMERICA
81 82 83 84 9 8 7 6 5 4 3 2 1
To Henry Kunkel and Jacques Oudin
for their discovery of idiotypy
Preface
Idiotypy is one of the most innovative concepts in modern immu-
nology, one which has constantly occupied the thoughts and labors of
many immunologists for the past twenty years. After the discovery of
antigenic individual specificities of human myeloma proteins, the con-
cept of idiotypy applied to conventional antibodies has stimulated
much research, with progress in several directions.
For several years, idiotypes were used as a tool to study the genetics
and structure of antibodies and the mechanisms of generation of anti-
body diversity. After 1970, the idiotypic determinants as phenotypic
markers of V region genes were used to identify the progeny of clones
reactive to a particular antigen. These studies led to the conclusion
that the same set of V genes encodes the specificity of the antigen-
binding receptor of Τ and Β lymphocytes. This concept opened the
way for a new field of investigation focused on the physiological sig-
nificance of idiotypes.
The discovery of autoanti-idiotype antibodies and of the antigen-
mimicking properties of anti-idiotype antibodies, and that the
idiotypic determinants borne by the lymphocyte's receptor serve as
regulatory sites, led to the formulation of the network theory. This
theory describes the immune system as a web of V domains in which
the clones speak to one another using an idiotype dictionary. These
numerous innovative concepts developed from the initial discovery of
idiotypy are still to be applied to the physiology and pathology of
lymphoid and nonlymphoid somatic cells. Therefore, we expect that
the idiotypic tool will be used in coming years to broaden our under-
xi
xii Preface
standing of the physiological host's defense immune reactions against
viruses, bacteria, parasites, and tumor cells and that anti-idiotypic
antibodies will be used to manipulate autoimmune diseases, age-related
immune phenomena, and undesirable immune reactions such as graft
rejection and hypersensitivity reactions.
The aims of this monograph are to present the progress made in the
study of the idiotypes of lymphocytes and the various experimental
findings demonstrating that a vast spectrum of possible relationships
between cells and antibodies and communications between various
subsets of Τ and Β lymphocytes exist within the immune system.
The findings which led to the elucidation of the suppression-
activation pathways of lymphocyte function as a result of the interac-
tion of the receptors with the anti-idiotypic antibodies are of prime
interest in the biomedical sciences. However, the complete elucida-
tion of the complexity of the relationships and communications be-
tween cells and the physiological significance and pathological implica-
tions of the immune network require new investigations in which the
immune functional network is dissected in detail.
We hope that the knowledge of the idiotypy of lymphocytes re-
viewed in this book will help the development of new directions in the
research of the idiotypy of antibodies, particularly on the role of the
idiotype-anti-idiotype reaction in various diseases. Our hopes are
based on the simple concept that "new" ideas emerge from "old"
observations and ideas.
I thank Monique and Alexandra for their help during the last two
years while I prepared the manuscript of this monograph.
C. Bona
La nature a mis toutes ses vérités
chacune en soi-même, notre art les
renferme les unes dans les autres,
mais cela n'est pas naturel: chacune
tient sa place.
Biaise Pascal, Pensées.
Ed. 1678, chapitre XXXI, 21.
Idiotypy—General Features
I. Introduction
The majority of biological effectors of protein origin, such as hor-
mones and enzymes, possess the ability to interact specifically with
cell receptors or substrates, and they are immunogenic. Similarly, the
antibody molecules, which represent the specific effectors of
antibody-forming cells, exhibit a dual character; they interact specifi-
cally with antigens and are immunogenic by virtue of their protein
nature as well as allotypic and idiotypic determinants.
The interaction with antigen is based on the extraordinary capacity
of the immune apparatus to produce combining sites complementary
to antigens. Recent estimates indicate that about 10 7 clones of
antibody-forming cells synthesize an equal number of combining sites
(Kabat, 1976). This extraordinary variability is contained in structural
differences of combining sites of immunoglobulin (Ig) molecules
which represent a segment of 5-34 Â. The combining site specificity
as well as its three-dimensional structure is the result of noncovalent
interactions between variable regions of the light and heavy chains of
Ig molecules. In fact, the first structural study of two Bence-Jones
myeloma proteins, which represent the light chain of Ig molecules
(Hilschman and Craig, 1965), showed that the light chain can be di-
vided into two regions: a variable region which differs in sequence
from one Bence-Jones protein to another, and a constant region which
1
2 1. Idiotypy—General Features
shows a similar sequence. New structural and molecular findings
clearly established that both heavy and light chains are composed of
four segments: variable (V), diversity (D), joining (J), and constant
(C). The genetic message of these regions is encoded by correspond-
ing genes.
The variable region of both the heavy and light chains is constituted
by three hypervariable and framework regions. The substitutions in
hypervariable regions account for the extraordinary variety of combin-
ing sites of antibody molecules.
Immunogenicity of the antibody molecule is related to the antigenic
determinants borne by both constant and variable regions of an-
tibodies. Discovery of allotypy (Oudin, I960) and localization of al-
lotypic determinants in the constant regions (Koshland, 1967; Prahl
and Porter, 1968) showed the immunogenic potency of antigenic de-
terminants associated with the constant region of Ig molecules in
homologous animals.
The discovery of idiotypy (Oudin and Michel, 1963; Kunkel et al.,
1963) and the localization of idiotypic determinants in the variable
regions (Grey et al., 1965; Wells et al., 1915) demonstrated the im-
munogenicity of antigenic determinants of the V region of Ig
molecules.
The ensuing years have seen the accumulation of several important
findings which show that idiotypic specificity is associated with a par-
ticular antigenic specificity of the antibody molecule. Resolution of
this observation proved to be a crucial discovery, providing new in-
sights about the diversity of antibodies and the regulation of the im-
mune response.
Idiotypy is defined as the property of an antibody of expressing
individual antigenic specificities both among antibodies of one indi-
vidual against different antigens and among antibodies of several indi-
viduals against the same antigen. The individual antigenic specificities
of Ig molecules were discovered by studying the immunogenicity of
human myeloma proteins. Slater, Ward, and Kunkel in 1955 reported
that rabbit antisera against one myeloma protein continued to react
with this protein after extensive absorption of the antisera on normal
Ig or other myeloma proteins. In 1963, Oudin and Michel in rabbits
and Kunkel et al. (1963) in man showed that each antibody which
interacted with a particular antigen expressed an individual antigenic
specificity. This individual antigenic specificity of the antibody
II. Anti-idiotypic Sera 3
molecule was called idiotype, a Greek name signifying individual form
or type, by Oudin and Michel (1969a).
II. Anti-idiotypic Sera
The idiotypes expressed on antibody molecules are defined roughly
by anti-idiotypic sera and more precisely by their structural correlates.
Anti-idiotypic sera can be obtained by immunization with antigen-
antibody complexes as Oudin and Michel (1963) prepared the anti-
idiotypic sera in rabbits, or with soluble, polymerized or carrier
coupled purified antibody or myeloma protein. Specificity of anti-
idiotypic sera obtained by these various methods of immunization is
very variable, since Β cells which are able to make anti-idiotypic an-
tibodies recognize many different idiotypes carried by the antibody
molecule. Thus, Jorgensen et al. (1977) studied the specificity of anti-
idiotypic antibodies produced by BALB/c mice after immunization
with MOPC315 myeloma protein, either alone or affinity labeled with
bromoacetyl-DNP-L-lysine. MOPC315 myeloma protein binds DNP
and TNP haptens. After immunization with MOPC315 myeloma pro-
tein alone, an anti-Id serum was obtained which reacted with idiotypic
determinants associated with the combining site, since the reaction
between MOPC315 and anti-Id antibodies was inhibited by DNP
ligands. In contrast, after immunization with MOPC315 affinity
labeled with bromoacetyl-DNP-L-lysine, the anti-Id antibodies found
were directed against idiotypes not associated with the combining site
since the binding of these antibodies to MOPC315 was not inhibited
by DNP-ligands. Similar results were obtained by Klaus (1978) after
immunization with a complex of KLH-DNP mixed in various ratios
with MOPC315. However, there is no general rule according to which
the antibody-antigen complex induces synthesis of anti-Id antibodies
against idiotypes associated with framework residues, and soluble or
polymerized antibodies are able to induce synthesis of anti-idiotypic
antibodies specific for idiotypes associated with the combining site.
Four categories of anti-idiotypic sera can be obtained as follows:
1. Heterologous anti-idiotypic sera obtained by immunization
across species barriers
2. Homologous anti-idiotypic sera obtained by immunization across
strain barriers
